FDA Approves Abemaciclib for HR+/HER2- Breast Cancer

The FDA approved abemaciclib (Verzenio) for use in combination with fulvestrant in women with HR+/HER2- advanced breast cancer with disease progression following endocrine therapy. The CDK4/6 inhibitor has also been approved as a monotherapy for patients with HR+/HER2- breast cancer with metastatic disease who have previously received endocrine therapy and chemotherapy.

Support for the combination indication comes from the phase III MONARCH 2 trial, in which adding abemaciclib to fulvestrant reduced the risk of disease progression or death by 45% versus fulvestrant alone.1 The single-agent approval is based on the single-arm phase II MONARCH 1 trial, in which the median progression-free survival (PFS) in this patient population was 6 months (95% CI 4.2-7.5) and the median overall survival (OS) was 17.7 months (95% CI, 16 to not reached).2

"Verzenio provides a new targeted treatment option for certain patients with breast cancer who are not responding to treatment, and unlike other drugs in the class, it can be given as a stand-alone treatment to patients who were previously treated with endocrine therapy and chemotherapy," Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a statement.

In the international, double-blind phase III MONARCH 2 trial, 669 patients were randomized in a 2:1 ratio to abemaciclib plus fulvestrant (n = 446) or fulvestrant plus placebo (n = 223). Patients had progressed during neoadjuvant or adjuvant endocrine therapy, within 12 months of adjuvant endocrine therapy, or during frontline endocrine treatment for metastatic disease. Individuals were excluded from enrollment if they were administered chemotherapy or more than 1 endocrine therapy in the metastatic setting.

Patient characteristics were well-balanced between the 2 arms. Overall, 82% of patients were postmenopausal, 72% had measurable disease, 56% had visceral disease, and 25% had primary endocrine therapy resistance. About 60% of patients had received chemotherapy in the adjuvant or neoadjuvant setting.

Patients received 500 mg (per label) of fulvestrant plus placebo or 150 mg of abemaciclib twice daily. The initial abemaciclib dose was 200 mg twice daily; however, the dose was amended after the first 178 patients were enrolled, due to diarrhea-related toxicity concerns. A GnRH agonist was given to pre/perimenopausal patients. The primary endpoint for the trial was PFS. Secondary endpoints included OS, response, clinical benefit rate, and safety.

Following 379 PFS events in the intent-to-treat population, the median PFS was 16.4 months in the abemaciclib arm versus 9.3 months in the fulvestrant-alone group (HR, 0.553; 95% CI, 0.449-0.681; P <.0000001). The overall response rates (ORRs) among patients with measurable disease were 48.1% and 21.3% in the abemaciclib and control arms, respectively.

The 48.1% ORR in the abemaciclib cohort included a complete response rate of 3.5%. There were no complete responses in the control arm. The median duration of response was 25.6 months in the placebo arm and had not yet been reached in the fulvestrant arm. The OS data are not yet mature.

The most frequently reported grade 3 AEs in the abemaciclib versus fulvestrant-alone arms were neutropenia (23.6% vs 1.3%) and diarrhea (13.4% vs 0.4%). Grade 4 neutropenia occurred in 2.9% versus 0.4% of the abemaciclib and fulvestrant-alone groups, respectively. There were 3 deaths in the abemaciclib arm linked to treatment-related AEs, compared with none in the control arm.

The MONARCH 1 trial included 132 patients with HR+/HER2- metastatic breast cancer who progressed during or after endocrine therapy and chemotherapy. The median age was 58 years (range, 36-89), 44.7% of patients had an ECOG performance status of 1, 90.2% had visceral disease, and 85.6% had at least 2 metastatic sites. Patients with CNS metastases were excluded from enrollment.

Patients had received a median of 3 (range, 1-8) prior lines of therapy—including a median of 2 lines of chemotherapy—for metastatic disease. Sixty-seven patients (50.8%) had received fulvestrant in the metastatic setting. With chemotherapy, 68.9% (n = 91) of patients had received a taxane and 55.3 % (n = 73) of patients had received capecitabine in the metastatic setting.

Abemaciclib was administered at 200 mg orally every 12 hours on a continuous schedule until progression or unacceptable toxicity. At the 8-month interim analysis, 35.6% of patients had received at least 8 cycles of the CDK4/6 inhibitor.

The investigator-assessed, confirmed ORR was 19.7% (n = 26; 95% CI, 13.3-27.5), which included all partial responses (PR). The rate of patients with stable disease (SD) ≥6 months was 22.7%, leading to a clinical benefit rate (complete response + PR + SD ≥6 months) of 42.4%. The median time to response was 3.7 months and the median duration of response was 8.6 months. Thirty-four patients had progressive disease.

The most common non-laboratory, all-grade AEs were diarrhea (90.2%), fatigue (65.2%), nausea (64.4%), decreased appetite (45.5%), and abdominal pain (38.6%). The grade 3 rates of these events were 19.7% for diarrhea, 12.9% for fatigue, 4.5% for nausea, 3.0% for decreased appetite, and 2.3% for abdominal pain.

Leukopenia (27.4%) and neutropenia (22.3%) were the most common laboratory AEs. The only grade 4 AE of any kind in the trial was neutropenia, which occurred in 4.6% of patients.

Serious AEs occurred in 24.2% (n = 32) of patients, with AEs leading to treatment discontinuation in 7.6% (n = 10) of patients. Dose reductions were required for 49.2% of patients (n = 65). The most common reason for dose reductions were diarrhea (20.5%) and neutropenia (10.6%). There were 2 patient deaths during treatment and 1 patient death within 30 days after study discontinuation.